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Gut Microbes: The Gut Brain Connection

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Clinical Understanding of the Human Gut Microbiome

Abstract

A growing appreciation for the role of the gut microbiome in health and disease, coupled with recent advances in microbiome-related research, has emphasized the importance of the gut microbiota in regulating brain function and behavior. Increasing clinical and preclinical studies are strengthening the concept that the microbiota-gut-brain axis plays a central role in maintaining cellular homeostasis and contributes to the pathophysiology of numerous brain diseases. The modes of communication between the gut microbiota and the brain are slowly being uncovered and include immune signaling pathways, host-microbe interactions in the enteric nervous system, tryptophan metabolism, the vagus nerve, gut hormone signaling, and signaling via microbial metabolites such as short chain fatty acids (SCFA). Indeed, animal models have been of paramount importance in unravelling the role of the gut microbiota in modulating brain function and behavior. Altered gut microbiota compositions have been implicated in a myriad of conditions including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Future studies aim to focus on understanding the mechanistic links between the gut microbiota and the brain, enabling the development of novel therapeutic strategies for multifaceted central nervous system (CNS) disorders.

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References

  1. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164:337–40.

    Article  CAS  PubMed  Google Scholar 

  2. Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. Current understanding of the human microbiome. Nat Med. 2018;24:392–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Collins SM, Bercik P. Gut microbiota: intestinal bacteria influence brain activity in healthy humans. Nat Rev Gastroenterol Hepatol. 2013;10:326–7.

    Article  PubMed  Google Scholar 

  4. Cryan JF, Cryan JF, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O’Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The microbiota-gut-brain axis. Physiol Rev. 2019;99:1877–2013.

    Article  CAS  PubMed  Google Scholar 

  5. Sherwin E, Dinan TG, Cryan JF. Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann N Y Acad Sci. 2018;1420:5–25.

    Article  PubMed  Google Scholar 

  6. Human Microbiome Project Consortium. A framework for human microbiome research. Nature. 2012;486:215–21.

    Article  Google Scholar 

  7. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207–14.

    Article  Google Scholar 

  8. Integrative HMP (iHMP) Research Network Consortium. The Integrative Human Microbiome Project. Nature. 2019;569:641–8.

    Article  Google Scholar 

  9. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012;148:1258–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Feng Q, Chen WD, Wang YD. Gut microbiota: an integral moderator in health and disease. Front Microbiol. 2018;9:151.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 2010;90:859–904.

    Article  CAS  PubMed  Google Scholar 

  12. Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: regulation by the microbiome. Neurobiol Stress. 2017;7:124–36.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011;12:453–66.

    Article  CAS  PubMed  Google Scholar 

  14. Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 2009;6:306–14.

    Article  CAS  PubMed  Google Scholar 

  15. Bordenstein SR, Theis KR. Host biology in light of the microbiome: ten principles of holobionts and hologenomes. PLoS Biol. 2015;13:e1002226.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Gaulke CA, Arnold HK, Humphreys IR, Kembel SW, O’Dwyer JP, Sharpton TJ. Ecophylogenetics clarifies the evolutionary association between mammals and their gut microbiota. mBio. 2018;9:e01348-18.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Suzuki TA, Fitzstevens JL, Schmidt VT, Enav H, Huus KE, Mbong Ngwese M, Griesshamme A, Pfleiderer A, Adegbite BR, Zinsou JF, Esen M, Velavan TP, Adegnika AA, Song LH, Spector TD, Muehlbauer AL, Marchi N, Kang H, Maier L, Blekhman R, Ségurel L, Ko G, Youngblut ND, Kremsner P, Ley RE. Codiversification of gut microbiota with humans. Science. 2022;377:1328–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pasolli E, Asnicar F, Manara S, Zolfo M, Karcher N, Armanini F, Beghini F, Manghi P, Tett A, Ghensi P, Collado MC, Rice BL, Dulong C, Morgan XC, Golden CD, Quince C, Huttenhower C, Segata N. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell. 2019;176:649–62.e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial community variation in human body habitats across space and time. Science. 2009;326:1694–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O’Sullivan O, Fitzgerald GF, Deane J, O’Connor M, Harnedy N, O’Connor K, O’Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O’Toole PW. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488:178–84.

    Article  CAS  PubMed  Google Scholar 

  21. Roswall J, Olsson LM, Kovatcheva-Datchary P, Nilsson S, Tremaroli V, Simon MC, Kiilerich P, Akrami R, Kramer M, Uhlen M, Gummesson A, Kristiansen K, Dahlgren J, Backhed F. Developmental trajectory of the healthy human gut microbiota during the first 5 years of life. Cell Host Microbe. 2021;29:765–76.e3.

    Article  CAS  PubMed  Google Scholar 

  22. Salazar N, Arboleya S, Valdes L, Stanton C, Ross P, Ruiz L, Gueimonde M, de Los Reyes-Gavilan CG. The human intestinal microbiome at extreme ages of life. Dietary intervention as a way to counteract alterations. Front Genet. 2014;5:406.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hubel DH, Wiesel TN. The period of susceptibility to the physiological effects of unilateral eye closure in kittens. J Physiol. 1970;206:419–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alberini CM, Travaglia A. Infantile amnesia: a critical period of learning to learn and remember. J Neurosci. 2017;37:5783–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Werker JF, Hensch TK. Critical periods in speech perception: new directions. Annu Rev Psychol. 2015;66:173–96.

    Article  PubMed  Google Scholar 

  26. Borre YE, O’Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 2014;20:509–18.

    Article  PubMed  Google Scholar 

  27. Cowan CSM, Dinan TG, Cryan JF. Annual research review: critical windows—the microbiota-gut-brain axis in neurocognitive development. J Child Psychol Psychiatry. 2020;61:353–71.

    Article  PubMed  Google Scholar 

  28. Goyal MS, Venkatesh S, Milbrandt J, Gordon JI, Raichle ME. Feeding the brain and nurturing the mind: linking nutrition and the gut microbiota to brain development. Proc Natl Acad Sci U S A. 2015;112:14105–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005;6:877–88.

    Article  CAS  PubMed  Google Scholar 

  30. Collado MC, Segata N. Initial exploration of in utero microbial colonization. Nat Med. 2020;26(4):469–70.

    Article  CAS  PubMed  Google Scholar 

  31. Fujimura KE, Sitarik AR, Havstad S, Lin DL, Levan S, Fadrosh D, Panzer AR, Lamere B, Rackaityte E, Lukacs NW, Wegienka G, Boushey HA, Ownby DR, Zoratti EM, Levin AM, Johnson CC, Lynch SV. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med. 2016;22:1187–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kennedy KM, de Goffau MC, Perez-Muñoz ME, Arrieta M-C, Bäckhed F, Bork P, Braun T, Bushman FD, Dore J, de Vos WM, Earl AM, Eisen JA, Elovitz MA, Ganal-Vonarburg SC, Gänzle MG, Garrett WS, Hall LJ, Hornef MW, Huttenhower C, Konnikova L, Lebeer S, Macpherson AJ, Massey RC, McHardy AC, Koren O, Lawley TD, Ley RE, O’Mahony L, O’Toole PW, Pamer EG, Parkhill J, Raes J, Rattei T, Salonen A, Segal E, Segata N, Shanahan F, Sloboda DM, Smith GCS, Sokol H, Spector TD, Surette MG, Tannock GW, Walker AW, Yassour M, Walter J. Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies. Nature. 2023;613:639–49.

    Article  CAS  PubMed  Google Scholar 

  33. Perez-Munoz ME, Arrieta MC, Ramer-Tait AE, Walter J. A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome. 2017;5:48.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Rackaityte E, Halkias J, Fukui EM, Mendoza VF, Hayzelden C, Crawford ED, Fujimura KE, Burt TD, Lynch SV. Viable bacterial colonization is highly limited in the human intestine in utero. Nat Med. 2020;26(4):599–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Walker RW, Clemente JC, Peter I, Loos RJF. The prenatal gut microbiome: are we colonized with bacteria in utero? Pediatr Obes. 2017;12(Suppl 1):3–17.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Walter J, Hornef MW. A philosophical perspective on the prenatal in utero microbiome debate. Microbiome. 2021;9:5.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ferretti P, Pasolli E, Tett A, Asnicar F, Gorfer V, Fedi S, Armanini F, Truong DT, Manara S, Zolfo M, Beghini F, Bertorelli R, De Sanctis V, Bariletti I, Canto R, Clementi R, Cologna M, Crifo T, Cusumano G, Gottardi S, Innamorati C, Mase C, Postai D, Savoi D, Duranti S, Lugli GA, Mancabelli L, Turroni F, Ferrario C, Milani C, Mangifesta M, Anzalone R, Viappiani A, Yassour M, Vlamakis H, Xavier R, Collado CM, Koren O, Tateo S, Soffiati M, Pedrotti A, Ventura M, Huttenhower C, Bork P, Segata N. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe. 2018;24:133–45.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yassour M, Jason E, Hogstrom LJ, Arthur TD, Tripathi S, Siljander H, Selvenius J, Oikarinen S, Hyoty H, Virtanen SM, Ilonen J, Ferretti P, Pasolli E, Tett A, Asnicar F, Segata N, Vlamakis H, Lander ES, Huttenhower C, Knip M, Xavier RJ. Strain-level analysis of mother-to-child bacterial transmission during the first few months of life. Cell Host Microbe. 2018;24:146–54.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gareau MG. Microbiota-gut-brain axis and cognitive function. Adv Exp Med Biol. 2014;817:357–71.

    Article  CAS  PubMed  Google Scholar 

  40. Luczynski P, McVey Neufeld KA, Oriach CS, Clarke G, Dinan TG, Cryan JF. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol. 2016;19:pyw020.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015;17:565–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Spichak S, Guzzetta KE, O’Leary OF, Clarke G, Dinan TG, Cryan JF. Without a bug’s life: germ-free rodents to interrogate microbiota-gut-neuroimmune interactions. Drug Discov Today Dis Model. 2018;28:79–93.

    Article  Google Scholar 

  43. Vuong HE, Pronovost GN, Williams DW, Coley EJL, Siegler EL, Qiu A, Kazantsev M, Wilson CJ, Rendon T, Hsiao EY. The maternal microbiome modulates fetal neurodevelopment in mice. Nature. 2020;586:281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O’Leary OF. Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry. 2015;78:e7–9.

    Article  PubMed  Google Scholar 

  45. Hoban AE, Stilling RM, Ryan FJ, Shanahan F, Dinan TG, Claesson MJ, Clarke G, Cryan JF. Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry. 2016;6:e774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lynch CMK, Nagpal J, Clarke G, Cryan JF. Wrapping things up: recent developments in understanding the role of the microbiome in regulating myelination. Curr Opin Physiol. 2021;23:100468.

    Article  CAS  Google Scholar 

  47. Luczynski P, Whelan SO, O’Sullivan C, Clarke G, Shanahan F, Dinan TG, Cryan JF. Adult microbiota-deficient mice have distinct dendritic morphological changes: differential effects in the amygdala and hippocampus. Eur J Neurosci. 2016;44:2654–66.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, Korecka A, Bakocevic N, Ng LG, Kundu P, Gulyas B, Halldin C, Hultenby K, Nilsson H, Hebert H, Volpe BT, Diamond B, Pettersson S. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014;6:263ra158.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Knox EG, Aburto MR, Tessier C, Nagpal J, Clarke G, O’Driscoll CM, Cryan JF. Microbial-derived metabolites induce actin cytoskeletal rearrangement and protect blood-brain barrier function. iScience. 2022;25:105648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Knox EG, Lynch CMK, Lee YS, O’Driscoll CM, Clarke G, Cryan JF, Aburto MR. The gut microbiota is important for the maintenance of blood-cerebrospinal fluid barrier integrity. Eur J Neurosci. 2023;57(2):233–41.

    Article  CAS  PubMed  Google Scholar 

  51. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18:666–73.

    Article  CAS  PubMed  Google Scholar 

  52. Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, Schwierzeck V, Utermohlen O, Chun E, Garrett WS, McCoy KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18:965–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lynch CMK, Clarke G, Cryan JF. Powering up microbiome-microglia interactions. Cell Metab. 2021;33:2097–9.

    Article  CAS  PubMed  Google Scholar 

  54. Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016;165:1762–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cirulli F, Musillo C, Berry A. Maternal obesity as a risk factor for brain development and mental health in the offspring. Neuroscience. 2020;447:122–35.

    Article  CAS  PubMed  Google Scholar 

  56. Jasarevic E, Bale TL. Prenatal and postnatal contributions of the maternal microbiome on offspring programming. Front Neuroendocrinol. 2019;55:100797.

    Article  CAS  PubMed  Google Scholar 

  57. Jasarevic E, Howard CD, Misic AM, Beiting DP, Bale TL. Stress during pregnancy alters temporal and spatial dynamics of the maternal and offspring microbiome in a sex-specific manner. Sci Rep. 2017;7:44182.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Jasarevic E, Howard CD, Morrison K, Misic A, Weinkopff T, Scott P, Hunter C, Beiting D, Bale TL. The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus. Nat Neurosci. 2018;21:1061–71.

    Article  CAS  PubMed  Google Scholar 

  59. Rincel M, Aubert P, Chevalier J, Grohard PA, Basso L, Monchaux de Oliveira C, Helbling JC, Levy E, Chevalier G, Leboyer M, Eberl G, Laye S, Capuron L, Vergnolle N, Neunlist M, Boudin H, Lepage P, Darnaudery M. Multi-hit early life adversity affects gut microbiota, brain and behavior in a sex-dependent manner. Brain Behav Immun. 2019;80:179–92.

    Article  PubMed  Google Scholar 

  60. Zijlmans MA, Korpela K, Riksen-Walraven JM, de Vos WM, de Weerth C. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology. 2015;53:233–45.

    Article  PubMed  Google Scholar 

  61. Korpela K, de Vos WM. Early life colonization of the human gut: microbes matter everywhere. Curr Opin Microbiol. 2018;44:70–8.

    Article  PubMed  Google Scholar 

  62. Stewart CJ, Ajami NJ, O’Brien JL, Hutchinson DS, Smith DP, Wong MC, Ross MC, Lloyd RE, Doddapaneni H, Metcalf GA, Muzny D, Gibbs RA, Vatanen T, Huttenhower C, Xavier RJ, Rewers M, Hagopian W, Toppari J, Ziegler AG, She JX, Akolkar B, Lernmark A, Hyoty H, Vehik K, Krischer JP, Petrosino JF. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature. 2018;562:583–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Derrien M, Alvarez AS, de Vos WM. The gut microbiota in the first decade of life. Trends Microbiol. 2019;27:997–1010.

    Article  CAS  PubMed  Google Scholar 

  64. Hollister EB, Riehle K, Luna RA, Weidler EM, Rubio-Gonzales M, Mistretta TA, Raza S, Doddapaneni HV, Metcalf GA, Muzny DM, Gibbs RA, Petrosino JF, Shulman RJ, Versalovic J. Structure and function of the healthy pre-adolescent pediatric gut microbiome. Microbiome. 2015;3:36.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107:11971–5.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Fouhy F, Watkins C, Hill CJ, O’Shea CA, Nagle B, Dempsey EM, O’Toole PW, Ross RP, Ryan CA, Stanton C. Perinatal factors affect the gut microbiota up to four years after birth. Nat Commun. 2019;10:1517.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Combellick JL, Shin H, Shin D, Cai Y, Hagan H, Lacher C, Lin DL, McCauley K, Lynch SV, Dominguez-Bello MG. Author correction: differences in the fecal microbiota of neonates born at home or in the hospital. Sci Rep. 2019;9:9044.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ho NT, Li F, Lee-Sarwar KA, Tun HM, Brown BP, Pannaraj PS, Bender JM, Azad MB, Thompson AL, Weiss ST, Azcarate-Peril MA, Litonjua AA, Kozyrskyj AL, Jaspan HB, Aldrovandi GM, Kuhn L. Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations. Nat Commun. 2018;9:4169.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Callaghan BL, Fields A, Gee DG, Gabard-Durnam L, Caldera C, Humphreys KL, Goff B, Flannery J, Telzer EH, Shapiro M, Tottenham N. Mind and gut: associations between mood and gastrointestinal distress in children exposed to adversity. Dev Psychopathol. 2020;32:309–28.

    Article  PubMed  Google Scholar 

  70. Gur TL, Worly BL, Bailey MT. Stress and the commensal microbiota: importance in parturition and infant neurodevelopment. Front Psychiatry. 2015;6:5.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Korpela K, Salonen A, Saxen H, Nikkonen A, Peltola V, Jaakkola T, de Vos W, Kolho KL. Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort. Pediatr Res. 2020;88(3):438–43.

    Article  CAS  PubMed  Google Scholar 

  72. O’Connor R, Moloney GM, Fulling C, O’Riordan KJ, Fitzgerald P, Bastiaanssen TFS, Schellekens H, Dinan TG, Cryan JF. Maternal antibiotic administration during a critical developmental window has enduring neurobehavioural effects in offspring mice. Behav Brain Res. 2021;404:113156.

    Article  PubMed  Google Scholar 

  73. Tun HM, Konya T, Takaro TK, Brook JR, Chari R, Field CJ, Guttman DS, Becker AB, Mandhane PJ, Turvey SE, Subbarao P, Sears MR, Scott JA, Kozyrskyj AL, CHILD Study Investigators. Exposure to household furry pets influences the gut microbiota of infant at 3-4 months following various birth scenarios. Microbiome. 2017;5:40.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Kan JM, Cowan CSM, Ooi CY, Kasparian NA. What can the gut microbiome teach us about the connections between child physical and mental health? A systematic review. Dev Psychobiol. 2019;61:700–13.

    Article  PubMed  Google Scholar 

  75. Codagnone MG, Spichak S, O’Mahony SM, O’Leary OF, Clarke G, Stanton C, Dinan TG, Cryan JF. Programming bugs: microbiota and the developmental origins of brain health and disease. Biol Psychiatry. 2019;85:150–63.

    Article  CAS  PubMed  Google Scholar 

  76. Milani C, Duranti S, Bottacini F, Casey E, Turroni F, Mahony J, Belzer C, Delgado Palacio S, Arboleya Montes S, Mancabelli L, Lugli GA, Rodriguez JM, Bode L, de Vos W, Gueimonde M, Margolles A, van Sinderen D, Ventura M. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota. Microbiol Mol Biol Rev. 2017;81:e00036-17.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Lynch CMK, Cowan CSM, Bastiaanssen TFS, Moloney GM, Theune N, van de Wouw M, Florensa Zanuy E, Ventura-Silva AP, Codagnone MG, Villalobos-Manriquez F, Segalla M, Koc F, Stanton C, Ross P, Dinan TG, Clarke G, Cryan JF. Critical windows of early-life microbiota disruption on behaviour, neuroimmune function, and neurodevelopment. Brain Behav Immun. 2022;108:309–27.

    Article  PubMed  Google Scholar 

  78. O’Mahony SM, Felice VD, Nally K, Savignac HM, Claesson MJ, Scully P, Woznicki J, Hyland NP, Shanahan F, Quigley EM, Marchesi JR, O’Toole PW, Dinan TG, Cryan JF. Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats. Neuroscience. 2014;277:885–901.

    Article  PubMed  Google Scholar 

  79. Verdu EF, Bercik P, Verma-Gandhu M, Huang XX, Blennerhassett P, Jackson W, Mao Y, Wang L, Rochat F, Collins SM. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55:182–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Moloney G, O’Connor R, Fulling C, O’Riordan KJ, Fitzgerald P, Bastiaanssen TFS, Schellekens H, Dinan TG, Cryan JF. Maternal antibiotic administration during a critical developmental window has enduring neurobehavioural effects in offspring mice. Behav Brain Res. 2021;404:113156.

    Article  PubMed  Google Scholar 

  81. O’Mahony SM, Clarke G, Dinan TG, Cryan JF. Early-life adversity and brain development: is the microbiome a missing piece of the puzzle? Neuroscience. 2017;342:37–54.

    Article  PubMed  Google Scholar 

  82. Carlson AL, Xia K, Azcarate-Peril MA, Goldman BD, Ahn M, Styner MA, Thompson AL, Geng X, Gilmore JH, Knickmeyer RC. Infant gut microbiome associated with cognitive development. Biol Psychiatry. 2018;83:148–59.

    Article  PubMed  Google Scholar 

  83. Gao W, Salzwedel AP, Carlson AL, Xia K, Azcarate-Peril MA, Styner MA, Thompson AL, Geng X, Goldman BD, Gilmore JH, Knickmeyer RC. Gut microbiome and brain functional connectivity in infants—a preliminary study focusing on the amygdala. Psychopharmacology. 2019;236:1641–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Aatsinki AK, Lahti L, Uusitupa HM, Munukka E, Keskitalo A, Nolvi S, O’Mahony S, Pietila S, Elo LL, Eerola E, Karlsson H, Karlsson L. Gut microbiota composition is associated with temperament traits in infants. Brain Behav Immun. 2019;80:849–58.

    Article  PubMed  Google Scholar 

  85. Christian LM, Galley JD, Hade EM, Schoppe-Sullivan S, Kamp Dush C, Bailey MT. Gut microbiome composition is associated with temperament during early childhood. Brain Behav Immun. 2015;45:118–27.

    Article  PubMed  Google Scholar 

  86. Loughman A, Ponsonby AL, O’Hely M, Symeonides C, Collier F, Tang MLK, Carlin J, Ranganathan S, Allen K, Pezic A, Saffery R, Jacka F, Harrison LC, Sly PD, Vuillermin P, BIS Investigator Group. Gut microbiota composition during infancy and subsequent behavioural outcomes. EBioMedicine. 2020;52:102640.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Firestein MR, Myers MM, Austin J, Stark RI, Barone JL, Ludwig RJ, Welch MG. Perinatal antibiotics alter preterm infant EEG and neurobehavior in the Family Nurture Intervention trial. Dev Psychobiol. 2019;61:661–9.

    Article  PubMed  Google Scholar 

  88. Sjogren YM, Tomicic S, Lundberg A, Bottacher MF, Bjorksten B, Sverremark-Ekstrom E, Jenmalm MC. Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Clin Exp Allergy. 2009;39:1842–51.

    Article  CAS  PubMed  Google Scholar 

  89. Sugino KY, Paneth N, Comstock SS. Michigan cohorts to determine associations of maternal pre-pregnancy body mass index with pregnancy and infant gastrointestinal microbial communities: late pregnancy and early infancy. PLoS One. 2019;14:e0213733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, Ballardini E, Bisceglia M, Cinquetti M, Brazzoduro E, Del Vecchio A, Tafuri S, Francavilla R. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 2014;168:228–33.

    Article  PubMed  Google Scholar 

  91. Partty A, Kalliomaki M, Wacklin P, Salminen S, Isolauri E. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res. 2015;77:823–8.

    Article  PubMed  Google Scholar 

  92. Callaghan BL, Cowan CS, Richardson R. Treating generational stress: effect of paternal stress on development of memory and extinction in offspring is reversed by probiotic treatment. Psychol Sci. 2016;27:1171–80.

    Article  PubMed  Google Scholar 

  93. Cowan CS, Callaghan BL, Richardson R. The effects of a probiotic formulation (Lactobacillus rhamnosus and L. helveticus) on developmental trajectories of emotional learning in stressed infant rats. Transl Psychiatry. 2016;6:e823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Cowan CSM, Stylianakis AA, Richardson R. Early-life stress, microbiota, and brain development: probiotics reverse the effects of maternal separation on neural circuits underpinning fear expression and extinction in infant rats. Dev Cogn Neurosci. 2019;37:100627.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Fukui H, Oshima T, Tanaka Y, Oikawa Y, Makizaki Y, Ohno H, Tomita T, Watari J, Miwa H. Effect of probiotic Bifidobacterium bifidum G9-1 on the relationship between gut microbiota profile and stress sensitivity in maternally separated rats. Sci Rep. 2018;8:12384.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Korpela K, Salonen A, Vepsalainen O, Suomalainen M, Kolmeder C, Varjosalo M, Miettinen S, Kukkonen K, Savilahti E, Kuitunen M, de Vos WM. Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants. Microbiome. 2018;6:182.

    Article  PubMed  PubMed Central  Google Scholar 

  98. O’Mahony SM, McVey Neufeld KA, Waworuntu RV, Pusceddu MM, Manurung S, Murphy K, Strain C, Laguna MC, Peterson VL, Stanton C, Berg BM, Dinan TG, Cryan JF. The enduring effects of early-life stress on the microbiota-gut-brain axis are buffered by dietary supplementation with milk fat globule membrane and a prebiotic blend. Eur J Neurosci. 2020;51:1042–58.

    Article  PubMed  Google Scholar 

  99. Guerville F, De Souto Barreto P, Ader I, Andrieu S, Casteilla L, Dray C, Fazilleau N, Guyonnet S, Langin D, Liblau R, Parini A, Valet P, Vergnolle N, Rolland Y, Vellas B. Revisiting the hallmarks of aging to identify markers of biological age. J Prev Alzheimers Dis. 2020;7:56–64.

    CAS  PubMed  Google Scholar 

  100. Konturek PC, Haziri D, Brzozowski T, Hess T, Heyman S, Kwiecien S, Konturek SJ, Koziel J. Emerging role of fecal microbiota therapy in the treatment of gastrointestinal and extra-gastrointestinal diseases. J Physiol Pharmacol. 2015;66:483–91.

    CAS  PubMed  Google Scholar 

  101. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Glimstedt G. The germfree animal as a research tool. Ann N Y Acad Sci. 1959;78:281–4.

    Article  CAS  PubMed  Google Scholar 

  103. Gustafsson B. Germ-free rearing of rats. Acta Anat (Basel). 1946;2:376–91.

    Article  PubMed  Google Scholar 

  104. Teng Y, Mu J, Xu F, Zhang X, Sriwastva MK, Liu QM, Li X, Lei C, Sundaram K, Hu X, Zhang L, Park JW, Hwang JY, Rouchka EC, Zhang X, Yan J, Merchant ML, Zhang H-G. Gut bacterial isoamylamine promotes age-related cognitive dysfunction by promoting microglial cell death. Cell Host Microbe. 2022;30:944–60.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ghosh TS, Shanahan F, O’Toole PW. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol. 2022;19:565–84.

    Article  PubMed  PubMed Central  Google Scholar 

  106. O’Toole PW, Jeffery IB. Gut microbiota and aging. Science. 2015;350:1214–5.

    Article  PubMed  Google Scholar 

  107. Vauzour D, Camprubi-Robles M, Miquel-Kergoat S, Andres-Lacueva C, Banati D, Barberger-Gateau P, Bowman GL, Caberlotto L, Clarke R, Hogervorst E, Kiliaan AJ, Lucca U, Manach C, Minihane AM, Mitchell ES, Perneczky R, Perry H, Roussel AM, Schuermans J, Sijben J, Spencer JP, Thuret S, van de Rest O, Vandewoude M, Wesnes K, Williams RJ, Williams RS, Ramirez M. Nutrition for the ageing brain: towards evidence for an optimal diet. Ageing Res Rev. 2017;35:222–40.

    Article  PubMed  Google Scholar 

  108. Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, Stanton C, van Sinderen D, O’Connor M, Harnedy N, O’Connor K, Henry C, O’Mahony D, Fitzgerald AP, Shanahan F, Twomey C, Hill C, Ross RP, O’Toole PW. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4586–91.

    Article  CAS  PubMed  Google Scholar 

  109. Ghosh TS, Das M, Jeffery IB, O’Toole PW. Adjusting for age improves identification of gut microbiome alterations in multiple diseases. elife. 2020;9:e50240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, Earls JC, Zimmer A, Glusman G, Robinson M, Yurkovich JT, Kado DM, Cauley JA, Zmuda J, Lane NE, Magis AT, Lovejoy JC, Hood L, Gibbons SM, Orwoll ES, Price ND. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021;3:274–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Boehme M, van de Wouw M, Bastiaanssen TFS, Olavarria-Ramirez L, Lyons K, Fouhy F, Golubeva AV, Moloney GM, Minuto C, Sandhu KV, Scott KA, Clarke G, Stanton C, Dinan TG, Schellekens H, Cryan JF. Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome. Mol Psychiatry. 2020;25(10):2567–83.

    Article  PubMed  Google Scholar 

  112. Ostlund-Lagerstrom L, Kihlgren A, Repsilber D, Bjorksten B, Brummer RJ, Schoultz I. Probiotic administration among free-living older adults: a double blinded, randomized, placebo-controlled clinical trial. Nutr J. 2016;15:80.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Ghosh TS, Rampelli S, Jeffery IB, Santoro A, Neto M, Capri M, Giampieri E, Jennings A, Candela M, Turroni S, Zoetendal EG, Hermes GDA, Elodie C, Meunier N, Brugere CM, Pujos-Guillot E, Berendsen AM, De Groot L, Feskins EJM, Kaluza J, Pietruszka B, Bielak MJ, Comte B, Maijo-Ferre M, Nicoletti C, De Vos WM, Fairweather-Tait S, Cassidy A, Brigidi P, Franceschi C, O’Toole PW. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut. 2020;69(7):1218–28.

    Article  CAS  PubMed  Google Scholar 

  114. Cox LM, Schafer MJ, Sohn J, Vincentini J, Weiner HL, Ginsberg SD, Blaser MJ. Calorie restriction slows age-related microbiota changes in an Alzheimer’s disease model in female mice. Sci Rep. 2019;9:17904.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012;489:318–21.

    Article  CAS  PubMed  Google Scholar 

  116. Rusli F, Boekschoten MV, Borelli V, Sun C, Lute C, Menke AL, van den Heuvel J, Salvioli S, Franceschi C, Muller M, Steegenga WT. Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age. Aging Cell. 2018;17:e12696.

    Article  PubMed  Google Scholar 

  117. Boehme M, Guzzetta KE, Bastiaanssen TFS, van de Wouw M, Moloney GM, Gual-Grau A, Spichak S, Olavarría-Ramírez L, Fitzgerald P, Morillas E, Ritz NL, Jaggar M, Cowan CSM, Crispie F, Donoso F, Halitzki E, Neto MC, Sichetti M, Golubeva AV, Fitzgerald RS, Claesson MJ, Cotter PD, O’Leary OF, Dinan TG, Cryan JF. Microbiota from young mice counteracts selective age-associated behavioral deficits. Nature Aging. 2021;1:666–76.

    Article  PubMed  Google Scholar 

  118. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14:576–90.

    Article  CAS  PubMed  Google Scholar 

  119. Prenderville JA, Kennedy PJ, Dinan TG, Cryan JF. Adding fuel to the fire: the impact of stress on the ageing brain. Trends Neurosci. 2015;38:13–25.

    Article  CAS  PubMed  Google Scholar 

  120. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, Loukov D, Schenck LP, Jury J, Foley KP, Schertzer JD, Larche MJ, Davidson DJ, Verdu EF, Surette MG, Bowdish DME. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2018;23:570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Esposito P, Chandler N, Kandere K, Basu S, Jacobson S, Connolly R, Tutor D, Theoharides TC. Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther. 2002;303:1061–6.

    Article  CAS  PubMed  Google Scholar 

  122. Kelly JR, Borre Y, O’Brien C, Patterson E, El Aidy S, Deane J, Kennedy PJ, Beers S, Scott K, Moloney G, Hoban AE, Scott L, Fitzgerald P, Ross P, Stanton C, Clarke G, Cryan JF, Dinan TG. Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016;82:109–18.

    Article  PubMed  Google Scholar 

  123. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Erny D, Prinz M. How microbiota shape microglial phenotypes and epigenetics. Glia. 2020;68(8):1655–72.

    Article  PubMed  Google Scholar 

  125. Parker A, Romano S, Ansorge R, Aboelnour A, Le Gall G, Savva GM, Pontifex MG, Telatin A, Baker D, Jones E, Vauzour D, Rudder S, Blackshaw LA, Jeffery G, Carding SR. Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome. 2022;10:68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Fulling C, Dinan TG, Cryan JF. Gut microbe to brain signaling: what happens in vagus. Neuron. 2019;101:998–1002.

    Article  CAS  PubMed  Google Scholar 

  127. Whitlock FA. Some psychiatric consequences of gastreotomy. Br Med J. 1961;1:1560–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Liu B, Fang F, Pedersen NL, Tillander A, Ludvigsson JF, Ekbom A, Svenningsson P, Chen H, Wirdefeldt K. Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology. 2017;88:1996–2002.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sorensen HT. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol. 2015;78:522–9.

    Article  PubMed  Google Scholar 

  130. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.

    Article  CAS  PubMed  Google Scholar 

  131. Breit S, Kupferberg A, Rogler G, Hasler G. Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Front Psychiatry. 2018;9:44.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011;108:16050–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron. 2019;101:246–59.e6.

    Article  CAS  PubMed  Google Scholar 

  134. Ye L, Bae M, Cassilly CD, Jabba SV, Thorpe DW, Martin AM, Lu H-Y, Wang J, Thompson JD, Lickwar CR. Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways. Cell Host Microbe. 2021;29:179–96.e9.

    Article  CAS  PubMed  Google Scholar 

  135. Muller PA, Schneeberger M, Matheis F, Wang P, Kerner Z, Ilanges A, Pellegrino K, Del Mármol J, Castro TBR, Furuichi M, Perkins M, Han W, Rao A, Pickard AJ, Cross JR, Honda K, de Araujo I, Mucida D. Microbiota modulate sympathetic neurons via a gut–brain circuit. Nature. 2020;583:441–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jaglin M, Rhimi M, Philippe C, Pons N, Bruneau A, Goustard B, Daugé V, Maguin E, Naudon L, Rabot S. Indole, a signaling molecule produced by the gut microbiota, negatively impacts emotional behaviors in rats. Front Neurosci. 2018;12:216.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Han W, Tellez LA, Perkins MH, Perez IO, Qu T, Ferreira J, Ferreira TL, Quinn D, Liu ZW, Gao XB, Kaelberer MM, Bohorquez DV, Shammah-Lagnado SJ, de Lartigue G, de Araujo IE. A neural circuit for gut-induced reward. Cell. 2018;175:665–78.e23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Suarez AN, Hsu TM, Liu CM, Noble EE, Cortella AM, Nakamoto EM, Hahn JD, de Lartigue G, Kanoski SE. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways. Nat Commun. 2018;9:2181.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Chen Y, Xu J, Chen Y. Regulation of neurotransmitters by the gut microbiota and effects on cognition in neurological disorders. Nutrients. 2021;13:2099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Gheorghe CE, Martin JA, Manriquez FV, Dinan TG, Cryan JF, Clarke G. Focus on the essentials: tryptophan metabolism and the microbiome-gut-brain axis. Curr Opin Pharmacol. 2019;48:137–45.

    Article  CAS  PubMed  Google Scholar 

  141. Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience. 2010;170:1179–88.

    Article  CAS  PubMed  Google Scholar 

  142. Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, Nagler CR, Ismagilov RF, Mazmanian SK, Hsiao EY. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161:264–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohorquez DV. A gut-brain neural circuit for nutrient sensory transduction. Science. 2018;361:eaat5236.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Lyte M. Microbial endocrinology and the microbiota-gut-brain axis. Adv Exp Med Biol. 2014;817:3–24.

    Article  CAS  PubMed  Google Scholar 

  145. Lyte M. Microbial endocrinology: host-microbiota neuroendocrine interactions influencing brain and behavior. Gut Microbes. 2014;5:381–9.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Strandwitz P, Kim KH, Terekhova D, Liu JK, Sharma A, Levering J, McDonald D, Dietrich D, Ramadhar TR, Lekbua A, Mroue N, Liston C, Stewart EJ, Dubin MJ, Zengler K, Knight R, Gilbert JA, Clardy J, Lewis K. GABA-modulating bacteria of the human gut microbiota. Nat Microbiol. 2019;4:396–403.

    Article  CAS  PubMed  Google Scholar 

  147. Wan L, Ge WR, Zhang S, Sun YL, Wang B, Yang G. Case-control study of the effects of gut microbiota composition on neurotransmitter metabolic pathways in children with attention deficit hyperactivity disorder. Front Neurosci. 2020;14:127.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Gill PA, van Zelm MC, Muir JG, Gibson PR. Review article: short chain fatty acids as potential therapeutic agents in human gastrointestinal and inflammatory disorders. Aliment Pharmacol Ther. 2018;48:15–34.

    Article  CAS  PubMed  Google Scholar 

  149. Erny D, Dokalis N, Mezö C, Castoldi A, Mossad O, Staszewski O, Frosch M, Villa M, Fuchs V, Mayer A, Neuber J, Sosat J, Tholen S, Schilling O, Vlachos A, Blank T, Gomez de Agüero M, Macpherson AJ, Pearce EJ, Prinz M. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metab. 2021;33:2260–76.e7.

    Article  CAS  PubMed  Google Scholar 

  150. Erny D, Hrabe de Angelis AL, Prinz M. Communicating systems in the body: how microbiota and microglia cooperate. Immunology. 2017;150:7–15.

    Article  CAS  PubMed  Google Scholar 

  151. Tahara Y, Yamazaki M, Sukigara H, Motohashi H, Sasaki H, Miyakawa H, Haraguchi A, Ikeda Y, Fukuda S, Shibata S. Gut microbiota-derived short chain fatty acids induce circadian clock entrainment in mouse peripheral tissue. Sci Rep. 2018;8:1395.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11:577–91.

    Article  CAS  PubMed  Google Scholar 

  153. van de Wouw M, Boehme M, Lyte JM, Wiley N, Strain C, O’Sullivan O, Clarke G, Stanton C, Dinan TG, Cryan JF. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations. J Physiol. 2018;596:4923–44.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019;16:461–78.

    Article  PubMed  Google Scholar 

  155. Hopfner F, Kunstner A, Muller SH, Kunzel S, Zeuner KE, Margraf NG, Deuschl G, Baines JF, Kuhlenbaumer G. Gut microbiota in Parkinson disease in a northern German cohort. Brain Res. 2017;1667:41–5.

    Article  CAS  PubMed  Google Scholar 

  156. Li W, Wu X, Hu X, Wang T, Liang S, Duan Y, Jin F, Qin B. Structural changes of gut microbiota in Parkinson’s disease and its correlation with clinical features. Sci China Life Sci. 2017;60:1223–33.

    Article  PubMed  Google Scholar 

  157. Morita C, Tsuji H, Hata T, Gondo M, Takakura S, Kawai K, Yoshihara K, Ogata K, Nomoto K, Miyazaki K, Sudo N. Gut dysbiosis in patients with anorexia nervosa. PLoS One. 2015;10:e0145274.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Schwiertz A, Taras D, Schafer K, Beijer S, Bos NA, Donus C, Hardt PD. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring). 2010;18:190–5.

    Article  PubMed  Google Scholar 

  159. Skonieczna-Zydecka K, Grochans E, Maciejewska D, Szkup M, Schneider-Matyka D, Jurczak A, Loniewski I, Kaczmarczyk M, Marlicz W, Czerwinska-Rogowska M, Pelka-Wysiecka J, Dec K, Stachowska E. Faecal short chain fatty acids profile is changed in Polish depressive women. Nutrients. 2018;10:1939.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Michels N, Van de Wiele T, De Henauw S. Chronic psychosocial stress and gut health in children: associations with calprotectin and fecal short-chain fatty acids. Psychosom Med. 2017;79:927–35.

    Article  CAS  PubMed  Google Scholar 

  161. Liu S, Li E, Sun Z, Fu D, Duan G, Jiang M, Yu Y, Mei L, Yang P, Tang Y, Zheng P. Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Sci Rep. 2019;9:287.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Paul B, Barnes S, Demark-Wahnefried W, Morrow C, Salvador C, Skibola C, Tollefsbol TO. Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin Epigenetics. 2015;7:112.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain & behaviour—epigenetic regulation of the gut-brain axis. Genes Brain Behav. 2014;13:69–86.

    Article  CAS  PubMed  Google Scholar 

  164. Ratsika A, Cruz Pereira JS, Lynch CMK, Clarke G, Cryan JF. Microbiota-immune-brain interactions: a lifespan perspective. Curr Opin Neurobiol. 2023;78:102652.

    Article  CAS  PubMed  Google Scholar 

  165. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020;30:492–506.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Benakis C, Brea D, Caballero S, Faraco G, Moore J, Murphy M, Sita G, Racchumi G, Ling L, Pamer EG, Iadecola C, Anrather J. Commensal microbiota affects ischemic stroke outcome by regulating intestinal gammadelta T cells. Nat Med. 2016;22:516–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Duc D, Vigne S, Bernier-Latmani J, Yersin Y, Ruiz F, Gaia N, Leo S, Lazarevic V, Schrenzel J, Petrova TV, Pot C. Disrupting myelin-specific Th17 cell gut homing confers protection in an adoptive transfer experimental autoimmune encephalomyelitis. Cell Rep. 2019;29:378–90.e4.

    Article  CAS  PubMed  Google Scholar 

  168. Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4615–22.

    Article  CAS  PubMed  Google Scholar 

  169. Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, Kasper LH. Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol. 2009;183:6041–50.

    Article  CAS  PubMed  Google Scholar 

  170. Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G, Eberl G, Snel J, Kelly D, Cerf-Bensussan N. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity. 2009;31:677–89.

    Article  CAS  PubMed  Google Scholar 

  171. Low D, Ginhoux F. Recent advances in the understanding of microglial development and homeostasis. Cell Immunol. 2018;330:68–78.

    Article  CAS  PubMed  Google Scholar 

  172. Thion MS, Low D, Silvin A, Chen J, Grisel P, Schulte-Schrepping J, Blecher R, Ulas T, Squarzoni P, Hoeffel G, Coulpier F, Siopi E, David FS, Scholz C, Shihui F, Lum J, Amoyo AA, Larbi A, Poidinger M, Buttgereit A, Lledo PM, Greter M, Chan JKY, Amit I, Beyer M, Schultze JL, Schlitzer A, Pettersson S, Ginhoux F, Garel S. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell. 2018;172:500–16.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. El Aidy S, Dinan TG, Cryan JF. Immune modulation of the brain-gut-microbe axis. Front Microbiol. 2014;5:146.

    PubMed  PubMed Central  Google Scholar 

  174. Da Mesquita S, Fu Z, Kipnis J. The meningeal lymphatic system: a new player in neurophysiology. Neuron. 2018;100:375–88.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke G, Stanton C, Dinan TG, Cryan JF. Targeting the microbiota-gut-brain axis: prebiotics have anxiolytic and antidepressant-like effects and reverse the impact of chronic stress in mice. Biol Psychiatry. 2017;82:472–87.

    Article  CAS  PubMed  Google Scholar 

  176. Luczynski P, Tramullas M, Viola M, Shanahan F, Clarke G, O’Mahony S, Dinan TG, Cryan JF. Microbiota regulates visceral pain in the mouse. elife. 2017;6:e25887.

    Article  PubMed  PubMed Central  Google Scholar 

  177. O’Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, O’Sullivan GC, Kiely B, Collins JK, Shanahan F, Quigley EM. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128:541–51.

    Article  PubMed  Google Scholar 

  178. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety. 2013;30:297–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Chu AL, Stochl J, Lewis G, Zammit S, Jones PB, Khandaker GM. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav Immun. 2019;76:74–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Khandaker GM, Zammit S, Burgess S, Lewis G, Jones PB. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain Behav Immun. 2018;69:264–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. van Sadelhoff JHJ, Perez Pardo P, Wu J, Garssen J, van Bergenhenegouwen J, Hogenkamp A, Hartog A, Kraneveld AD. The gut-immune-brain axis in autism spectrum disorders; a focus on amino acids. Front Endocrinol (Lausanne). 2019;10:247.

    Article  PubMed  Google Scholar 

  182. Cosorich I, Dalla-Costa G, Sorini C, Ferrarese R, Messina MJ, Dolpady J, Radice E, Mariani A, Testoni PA, Canducci F, Comi G, Martinelli V, Falcone M. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017;3:e1700492.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Kang DW, Adams JB, Coleman DM, Pollard EL, Maldonado J, McDonough-Means S, Caporaso JG, Krajmalnik-Brown R. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Sci Rep. 2019;9:5821.

    Article  PubMed  PubMed Central  Google Scholar 

  184. McGaughey KD, Yilmaz-Swenson T, Elsayed NM, Cruz DA, Rodriguiz RM, Kritzer MD, Peterchev AV, Roach J, Wetsel WC, Williamson DE. Relative abundance of Akkermansia spp. and other bacterial phylotypes correlates with anxiety- and depressive-like behavior following social defeat in mice. Sci Rep. 2019;9:3281.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, Ferrari C, Guerra UP, Paghera B, Muscio C, Bianchetti A, Volta GD, Turla M, Cotelli MS, Gennuso M, Prelle A, Zanetti O, Lussignoli G, Mirabile D, Bellandi D, Gentile S, Belotti G, Villani D, Harach T, Bolmont T, Padovani A, Boccardi M, Frisoni GB, INDIA-FBP Group. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60–8.

    Article  CAS  PubMed  Google Scholar 

  186. Perez-Pardo P, Dodiya HB, Engen PA, Forsyth CB, Huschens AM, Shaikh M, Voigt RM, Naqib A, Green SJ, Kordower JH, Shannon KM, Garssen J, Kraneveld AD, Keshavarzian A. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut. 2019;68:829–43.

    Article  CAS  PubMed  Google Scholar 

  187. Peter I, Dubinsky M, Bressman S, Park A, Lu C, Chen N, Wang A. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 2018;75:939–46.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Frankiensztajn LM, Elliott E, Koren O. The microbiota and the hypothalamus-pituitary-adrenocortical (HPA) axis, implications for anxiety and stress disorders. Curr Opin Neurobiol. 2020;62:76–82.

    Article  CAS  PubMed  Google Scholar 

  189. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004;558:263–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Lyte JM, Gheorghe CE, Goodson MS, Kelley-Loughnane N, Dinan TG, Cryan JF, Clarke G. Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent. Neurogastroenterol Motil. 2020;32:e13881.

    Article  CAS  PubMed  Google Scholar 

  192. O’Mahony SM, Hyland NP, Dinan TG, Cryan JF. Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology. 2011;214:71–88.

    Article  PubMed  Google Scholar 

  193. De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ, Green W, Denou E, Silva MA, Santacruz A, Sanz Y, Surette MG, Verdu EF, Collins SM, Bercik P. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun. 2015;6:7735.

    Article  PubMed  Google Scholar 

  194. De Weerth C. Do bacteria shape our development? Crosstalk between intestinal microbiota and HPA axis. Neurosci Biobehav Rev. 2017;83:458–71.

    Article  PubMed  Google Scholar 

  195. Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S, O’Mahony L, O’Mahony S, Shanahan F, Keeling PW. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology. 2006;130:304–11.

    Article  CAS  PubMed  Google Scholar 

  196. Cryan JF, O’Riordan KJ, Sandhu K, Peterson V, Dinan TG. The gut microbiome in neurological disorders. Lancet Neurol. 2020;19:179–94.

    Article  CAS  PubMed  Google Scholar 

  197. Chaidez V, Hansen RL, Hertz-Picciotto I. Gastrointestinal problems in children with autism, developmental delays or typical development. J Autism Dev Disord. 2014;44:1117–27.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Hodges H, Fealko C, Soares N. Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation. Transl Pediatr. 2020;9:S55–65.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, McDonough-Means S, Pollard EL, Roux S, Sadowsky MJ, Lipson KS, Sullivan MB, Caporaso JG, Krajmalnik-Brown R. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017;5:10.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Mayer EA, Padua D, Tillisch K. Altered brain-gut axis in autism: comorbidity or causative mechanisms? BioEssays. 2014;36:933–9.

    Article  PubMed  Google Scholar 

  201. Golubeva AV, Joyce SA, Moloney G, Burokas A, Sherwin E, Arboleya S, Flynn I, Khochanskiy D, Moya-Perez A, Peterson V, Rea K, Murphy K, Makarova O, Buravkov S, Hyland NP, Stanton C, Clarke G, Gahan CGM, Dinan TG, Cryan JF. Microbiota-related changes in bile acid & tryptophan metabolism are associated with gastrointestinal dysfunction in a mouse model of autism. EBioMedicine. 2017;24:166–78.

    Article  PubMed  PubMed Central  Google Scholar 

  202. Needham BD, Funabashi M, Adame MD, Wang Z, Boktor JC, Haney J, Wu W-L, Rabut C, Ladinsky MS, Hwang S-J, Guo Y, Zhu Q, Griffiths JA, Knight R, Bjorkman PJ, Shapiro MG, Geschwind DH, Holschneider DP, Fischbach MA, Mazmanian SK. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature. 2022;602:647–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF. Microbiota is essential for social development in the mouse. Mol Psychiatry. 2014;19:146–8.

    Article  CAS  PubMed  Google Scholar 

  204. Sharon G, Cruz NJ, Kang DW, Gandal MJ, Wang B, Kim YM, Zink EM, Casey CP, Taylor BC, Lane CJ, Bramer LM, Isern NG, Hoyt DW, Noecker C, Sweredoski MJ, Moradian A, Borenstein E, Jansson JK, Knight R, Metz TO, Lois C, Geschwind DH, Krajmalnik-Brown R, Mazmanian SK. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell. 2019;177:1600–18.e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Brock J. Can gut bacteria cause autism (in mice)? June 14, 2019. medium.com. https://medium.com/dr-jon-brock/can-gut-bacteria-cause-autism-in-mice-582306fd7235.

  206. Kandeel WA, Meguid NA, Bjorklund G, Eid EM, Farid M, Mohamed SK, Wakeel KE, Chirumbolo S, Elsaeid A, Hammad DY. Impact of Clostridium bacteria in children with autism spectrum disorder and their anthropometric measurements. J Mol Neurosci. 2020;70(6):897–907.

    Article  CAS  PubMed  Google Scholar 

  207. Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, Longman RS, Honda K, Littman DR, Choi GB, Huh JR. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature. 2017;549:528–32.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000;15:429–35.

    Article  CAS  PubMed  Google Scholar 

  209. Russo AJ. Decreased plasma myeloperoxidase associated with probiotic therapy in autistic children. Clin Med Insights Pediatr. 2015;9:13–7.

    Article  PubMed  PubMed Central  Google Scholar 

  210. Tomova A, Husarova V, Lakatosova S, Bakos J, Vlkova B, Babinska K, Ostatnikova D. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav. 2015;138:179–87.

    Article  CAS  PubMed  Google Scholar 

  211. Yap CX, Henders AK, Alvares GA, Wood DL, Krause L, Tyson GW, Restuadi R, Wallace L, McLaren T, Hansell NK. Autism-related dietary preferences mediate autism-gut microbiome associations. Cell. 2021;184:5916–31.e17.

    Article  CAS  PubMed  Google Scholar 

  212. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011;479:538–41.

    Article  CAS  PubMed  Google Scholar 

  213. Tremlett H, Waubant E. Gut microbiome and pediatric multiple sclerosis. Mult Scler. 2018;24:64–8.

    Article  PubMed  Google Scholar 

  214. Tremlett H, Fadrosh DW, Faruqi AA, Zhu F, Hart J, Roalstad S, Graves J, Lynch S, Waubant E, US Network of Pediatric MS Centers Centers. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol. 2016;23:1308–21.

    Article  PubMed  PubMed Central  Google Scholar 

  215. Cantoni C, Lin Q, Dorsett Y, Ghezzi L, Liu Z, Pan Y, Chen K, Han Y, Li Z, Xiao H, Gormley M, Liu Y, Bokoliya S, Panier H, Suther C, Evans E, Deng L, Locca A, Mikesell R, Obert K, Newland P, Wu Y, Salter A, Cross AH, Tarr PI, Lovett-Racke A, Piccio L, Zhou Y. Alterations of host-gut microbiome interactions in multiple sclerosis. EBioMedicine. 2022;76:103798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Berer K, Gerdes LA, Cekanaviciute E, Jia X, Xiao L, Xia Z, Liu C, Klotz L, Stauffer U, Baranzini SE, Kumpfel T, Hohlfeld R, Krishnamoorthy G, Wekerle H. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017;114:10719–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, Kanner R, Bencosme Y, Lee YK, Hauser SL, Crabtree-Hartman E, Sand IK, Gacias M, Zhu Y, Casaccia P, Cree BAC, Knight R, Mazmanian SK, Baranzini SE. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017;114:10713–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Gacias M, Gaspari S, Santos PM, Tamburini S, Andrade M, Zhang F, Shen N, Tolstikov V, Kiebish MA, Dupree JL, Zachariou V, Clemente JC, Casaccia P. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. elife. 2016;5:e13442.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Keogh CE, Kim DHJ, Pusceddu MM, Knotts TA, Rabasa G, Sladek JA, Hsieh MT, Honeycutt M, Brust-Mascher I, Barboza M, Gareau MG. Myelin as a regulator of development of the microbiota-gut-brain axis. Brain Behav Immun. 2021;91:437–50.

    Article  CAS  PubMed  Google Scholar 

  220. Lu J, Synowiec S, Lu L, Yu Y, Bretherick T, Takada S, Yarnykh V, Caplan J, Caplan M, Claud EC, Drobyshevsky A. Microbiota influence the development of the brain and behaviors in C57BL/6J mice. PLoS One. 2018;13:e0201829.

    Article  PubMed  PubMed Central  Google Scholar 

  221. Libbey JE, Sanchez JM, Doty DJ, Sim JT, Cusick MF, Cox JE, Fischer KF, Round JL, Fujinami RS. Variations in diet cause alterations in microbiota and metabolites that follow changes in disease severity in a multiple sclerosis model. Benefic Microbes. 2018;9:495–513.

    Article  CAS  Google Scholar 

  222. Dargahi N, Matsoukas J, Apostolopoulos V. Streptococcus thermophilus ST285 alters pro-inflammatory to anti-inflammatory cytokine secretion against multiple sclerosis peptide in mice. Brain Sci. 2020;10:126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Kouchaki E, Tamtaji OR, Salami M, Bahmani F, Daneshvar Kakhaki R, Akbari E, Tajabadi-Ebrahimi M, Jafari P, Asemi Z. Clinical and metabolic response to probiotic supplementation in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Clin Nutr. 2017;36:1245–9.

    Article  CAS  PubMed  Google Scholar 

  224. Tamtaji OR, Kouchaki E, Salami M, Aghadavod E, Akbari E, Tajabadi-Ebrahimi M, Asemi Z. The effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr. 2017;36:660–5.

    Article  CAS  PubMed  Google Scholar 

  225. Tankou SK, Regev K, Healy BC, Tjon E, Laghi L, Cox LM, Kivisakk P, Pierre IV, Hrishikesh L, Gandhi R, Cook S, Glanz B, Stankiewicz J, Weiner HL. A probiotic modulates the microbiome and immunity in multiple sclerosis. Ann Neurol. 2018;83:1147–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Greenland JC, Williams-Gray CH, Barker RA. The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur J Neurosci. 2019;49:328–38.

    Article  PubMed  Google Scholar 

  227. Felice VD, Quigley EM, Sullivan AM, O’Keeffe GW, O’Mahony SM. Microbiota-gut-brain signalling in Parkinson’s disease: implications for non-motor symptoms. Parkinsonism Relat Disord. 2016;27:1–8.

    Article  PubMed  Google Scholar 

  228. Knudsen K, Krogh K, Ostergaard K, Borghammer P. Constipation in Parkinson’s disease: subjective symptoms, objective markers, and new perspectives. Mov Disord. 2017;32:94–105.

    Article  PubMed  Google Scholar 

  229. Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett. 2006;396:67–72.

    Article  CAS  PubMed  Google Scholar 

  230. Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One. 2011;6:e28032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Hilton D, Stephens M, Kirk L, Edwards P, Potter R, Zajicek J, Broughton E, Hagan H, Carroll C. Accumulation of alpha-synuclein in the bowel of patients in the pre-clinical phase of Parkinson’s disease. Acta Neuropathol. 2014;127:235–41.

    Article  CAS  PubMed  Google Scholar 

  232. Bhattacharyya D, Mohite GM, Krishnamoorthy J, Gayen N, Mehra S, Navalkar A, Kotler SA, Ratha BN, Ghosh A, Kumar R, Garai K, Mandal AK, Maji SK, Bhunia A. Lipopolysaccharide from gut microbiota modulates alpha-synuclein aggregation and alters its biological function. ACS Chem Neurosci. 2019;10:2229–36.

    Article  CAS  PubMed  Google Scholar 

  233. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, Wang ZY, Roybon L, Melki R, Li JY. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128:805–20.

    Article  PubMed  Google Scholar 

  234. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, Lee JH, Kim WR, Kook M, Foss CA, Shen C, Lee H, Kulkarni S, Pasricha PJ, Lee G, Pomper MG, Dawson VL, Dawson TM, Ko HS. Transneuronal propagation of pathologic alpha-synuclein from the gut to the brain models Parkinson’s disease. Neuron. 2019;103:627–41.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Aho VTE, Pereira PAB, Voutilainen S, Paulin L, Pekkonen E, Auvinen P, Scheperjans F. Gut microbiota in Parkinson’s disease: temporal stability and relations to disease progression. EBioMedicine. 2019;44:691–707.

    Article  PubMed  PubMed Central  Google Scholar 

  236. Heintz-Buschart A, Pandey U, Wicke T, Sixel-Doring F, Janzen A, Sittig-Wiegand E, Trenkwalder C, Oertel WH, Mollenhauer B, Wilmes P. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov Disord. 2018;33:88–98.

    Article  CAS  PubMed  Google Scholar 

  237. Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM. Colonic bacterial composition in Parkinson’s disease. Mov Disord. 2015;30:1351–60.

    Article  CAS  PubMed  Google Scholar 

  238. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015;30:350–8.

    Article  PubMed  Google Scholar 

  239. Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, Cui C, Shen YQ. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: gut microbiota, glial reaction and TLR4/TNF-alpha signaling pathway. Brain Behav Immun. 2018;70:48–60.

    Article  CAS  PubMed  Google Scholar 

  240. Challis C, Hori A, Sampson TR, Yoo BB, Challis RC, Hamilton AM, Mazmanian SK, Volpicelli-Daley LA, Gradinaru V. Gut-seeded alpha-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice. Nat Neurosci. 2020;23:327–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Wallen ZD, Demirkan A, Twa G, Cohen G, Dean MN, Standaert DG, Sampson TR, Payami H. Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Nat Commun. 2022;13:6958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167:1469–80.e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Burmann J, Fassbender K, Schwiertz A, Schafer KH. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66–72.

    Article  PubMed  Google Scholar 

  244. Sampson TR, Challis C, Jain N, Moiseyenko A, Ladinsky MS, Shastri GG, Thron T, Needham BD, Horvath I, Debelius JW, Janssen S, Knight R, Wittung-Stafshede P, Gradinaru V, Chapman M, Mazmanian SK. A gut bacterial amyloid promotes alpha-synuclein aggregation and motor impairment in mice. elife. 2020;9:e53111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Dobbs SM, Dobbs RJ, Weller C, Charlett A, Bjarnason IT, Lawson AJ, Letley D, Harbin L, Price AB, Ibrahim MA, Oxlade NL, Bowthorpe J, Leckstroem D, Smee C, Plant JM, Peterson DW. Differential effect of Helicobacter pylori eradication on time-trends in brady/hypokinesia and rigidity in idiopathic parkinsonism. Helicobacter. 2010;15:279–94.

    Article  PubMed  PubMed Central  Google Scholar 

  246. Shen X, Yang H, Wu Y, Zhang D, Jiang H. Meta-analysis: association of Helicobacter pylori infection with Parkinson’s diseases. Helicobacter. 2017;22

    Google Scholar 

  247. Vogt NM, Kerby RL, Dill-Mcfarland KA, Harding SJ, Merluzzi AP, Johnson SC, Carlsson CM, Asthana S, Zetterberg H, Blennow K, Bendlin BB, Rey FE. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7:13537.

    Article  PubMed  PubMed Central  Google Scholar 

  248. van Kessel SP, Frye AK, El-Gendy AO, Castejon M, Keshavarzian A, van Dijk G, El Aidy S. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease. Nat Commun. 2019;10:310.

    Article  PubMed  PubMed Central  Google Scholar 

  249. Friedland RP. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. J Alzheimers Dis. 2015;45:349–62.

    Article  CAS  PubMed  Google Scholar 

  250. Hill JM, Clement C, Pogue AI, Bhattacharjee S, Zhao Y, Lukiw WJ. Pathogenic microbes, the microbiome, and Alzheimer’s disease (AD). Front Aging Neurosci. 2014;6:127.

    PubMed  PubMed Central  Google Scholar 

  251. Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, Letenneur L, Lovheim H, Mancuso R, Miklossy J, Otth C, Palamara AT, Perry G, Preston C, Pretorius E, Strandberg T, Tabet N, Taylor-Robinson SD, Whittum-Hudson JA. Microbes and Alzheimer’s disease. J Alzheimers Dis. 2016;51:979–84.

    Article  PubMed  PubMed Central  Google Scholar 

  252. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010;5:e9505.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.

    Article  CAS  PubMed  Google Scholar 

  254. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, Gyorgy B, Breakefield XO, Tanzi RE, Moir RD. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron. 2018;99:56–63.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Itzhaki RF. Herpes simplex virus type 1 and Alzheimer’s disease: possible mechanisms and signposts. FASEB J. 2017;31:3216–26.

    Article  CAS  PubMed  Google Scholar 

  256. Harach T, Marungruang N, Duthilleul N, Cheatham V, McCoy KD, Frisoni G, Neher JJ, Fak F, Jucker M, Lasser T, Bolmont T. Reduction of abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Mezo C, Dokalis N, Mossad O, Staszewski O, Neuber J, Yilmaz B, Schnepf D, de Aguero MG, Ganal-Vonarburg SC, Macpherson AJ, Meyer-Luehmann M, Staeheli P, Blank T, Prinz M, Erny D. Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun. 2020;8:119.

    Article  PubMed  PubMed Central  Google Scholar 

  258. Dodiya HB, Kuntz T, Shaik SM, Baufeld C, Leibowitz J, Zhang X, Gottel N, Zhang X, Butovsky O, Gilbert JA, Sisodia SS. Sex-specific effects of microbiome perturbations on cerebral Abeta amyloidosis and microglia phenotypes. J Exp Med. 2019;216:1542–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Oyler-Castrillo P, Zhang X, Musch MW, Shen X, Jabri B, Chang EB, Tanzi RE, Sisodia SS. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1DeltaE9 murine model of Alzheimer’s disease. Sci Rep. 2017;7:10411.

    Article  PubMed  PubMed Central  Google Scholar 

  260. Zhuang ZQ, Shen LL, Li WW, Fu X, Zeng F, Gui L, Lu Y, Cai M, Zhu C, Tan YL, Zheng P, Li HY, Zhu J, Zhou HD, Bu XL, Wang YJ. Gut microbiota is altered in patients with Alzheimer’s disease. J Alzheimers Dis. 2018;63:1337–46.

    Article  CAS  PubMed  Google Scholar 

  261. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, Craft S, Gandy S, Buettner C, Stoeckel LE, Holtzman DM, Nathan DM. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14:168–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Nho K, Kueider-Paisley A, Mahmoudiandehkordi S, Arnold M, Risacher SL, Louie G, Blach C, Baillie R, Han X, Kastenmuller G, Jia W, Xie G, Ahmad S, Hankemeier T, van Duijn CM, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, Saykin AJ, Kaddurah-Daouk R, Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium. Altered bile acid profile in mild cognitive impairment and Alzheimer’s disease: relationship to neuroimaging and CSF biomarkers. Alzheimers Dement. 2019;15:232–44.

    Article  PubMed  Google Scholar 

  263. Connell E, Le Gall G, Pontifex MG, Sami S, Cryan JF, Clarke G, Müller M, Vauzour D. Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia. Mol Neurodegener. 2022;17:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Singh V, Roth S, Llovera G, Sadler R, Garzetti D, Stecher B, Dichgans M, Liesz A. Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci. 2016;36:7428–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT, Zhu JJ, You C, Chen Q, Zhou L, Pan SY, Zhou HW. Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc. 2015;4:e002699.

    Article  PubMed  PubMed Central  Google Scholar 

  266. Tan C, Wang H, Gao X, Xu R, Zeng X, Cui Z, Zhu J, Wu Q, Xia G, Zhou H, He Y, Yin J. Dynamic changes and prognostic value of gut microbiota-dependent trimethylamine-N-oxide in acute ischemic stroke. Front Neurol. 2020;11:29.

    Article  PubMed  PubMed Central  Google Scholar 

  267. Zhu C, Li G, Lv Z, Li J, Wang X, Kang J, Zhan C. Association of plasma trimethylamine-N-oxide levels with post-stroke cognitive impairment: a 1-year longitudinal study. Neurol Sci. 2020;41:57–63.

    Article  PubMed  Google Scholar 

  268. Houlden A, Goldrick M, Brough D, Vizi ES, Lenart N, Martinecz B, Roberts IS, Denes A. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production. Brain Behav Immun. 2016;57:10–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Xia GH, You C, Gao XX, Zeng XL, Zhu JJ, Xu KY, Tan CH, Xu RT, Wu QH, Zhou HW, He Y, Yin J. Stroke dysbiosis index (SDI) in gut microbiome are associated with brain injury and prognosis of stroke. Front Neurol. 2019;10:397.

    Article  PubMed  PubMed Central  Google Scholar 

  270. Winek K, Engel O, Koduah P, Heimesaat MM, Fischer A, Bereswill S, Dames C, Kershaw O, Gruber AD, Curato C, Oyama N, Meisel C, Meisel A, Dirnagl U. Depletion of cultivatable gut microbiota by broad-spectrum antibiotic pretreatment worsens outcome after murine stroke. Stroke. 2016;47:1354–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Sun J, Ling Z, Wang F, Chen W, Li H, Jin J, Zhang H, Pang M, Yu J, Liu J. Clostridium butyricum pretreatment attenuates cerebral ischemia/reperfusion injury in mice via anti-oxidation and anti-apoptosis. Neurosci Lett. 2016;613:30–5.

    Article  CAS  PubMed  Google Scholar 

  272. De Caro C, Iannone LF, Citraro R, Striano P, De Sarro G, Constanti A, Cryan JF, Russo E. Can we ‘seize’ the gut microbiota to treat epilepsy? Neurosci Biobehav Rev. 2019;107:750–64.

    Article  PubMed  Google Scholar 

  273. Cowan CSM, Hoban AE, Ventura-Silva AP, Dinan TG, Clarke G, Cryan JF. Gutsy moves: the amygdala as a critical node in microbiota to brain signaling. BioEssays. 2018;40.

    Google Scholar 

  274. Lindefeldt M, Eng A, Darban H, Bjerkner A, Zetterstrom CK, Allander T, Andersson B, Borenstein E, Dahlin M, Prast-Nielsen S. The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy. NPJ Biofilms Microbiomes. 2019;5:5.

    Article  PubMed  PubMed Central  Google Scholar 

  275. Xie G, Zhou Q, Qiu CZ, Dai WK, Wang HP, Li YH, Liao JX, Lu XG, Lin SF, Ye JH, Ma ZY, Wang WJ. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World J Gastroenterol. 2017;23:6164–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Newell C, Bomhof MR, Reimer RA, Hittel DS, Rho JM, Shearer J. Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder. Mol Autism. 2016;7:37.

    Article  PubMed  PubMed Central  Google Scholar 

  277. Rogawski MA, Loscher W, Rho JM. Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med. 2016;6:a022780.

    Article  PubMed  PubMed Central  Google Scholar 

  278. Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018;174:497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Braakman HMH, van Ingen J. Can epilepsy be treated by antibiotics? J Neurol. 2018;265:1934–6.

    Article  PubMed  Google Scholar 

  280. Testa CM, Jankovic J. Huntington disease: a quarter century of progress since the gene discovery. J Neurol Sci. 2019;396:52–68.

    Article  CAS  PubMed  Google Scholar 

  281. Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington’s disease: mechanisms of pathogenesis and therapeutic strategies. Cold Spring Harb Perspect Med. 2017;7(7):a024240.

    Article  PubMed  PubMed Central  Google Scholar 

  282. van Dellen A, Hannan AJ. Genetic and environmental factors in the pathogenesis of Huntington’s disease. Neurogenetics. 2004;5:9–17.

    Article  PubMed  Google Scholar 

  283. Rosas HD, Doros G, Bhasin S, Thomas B, Gevorkian S, Malarick K, Matson W, Hersch SM. A systems-level “misunderstanding”: the plasma metabolome in Huntington’s disease. Ann Clin Transl Neurol. 2015;2:756–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Radulescu CI, Garcia-Miralles M, Sidik H, Bardile CF, Yusof N, Lee HU, Ho EXP, Chu CW, Layton E, Low D, De Sessions PF, Pettersson S, Ginhoux F, Pouladi MA. Manipulation of microbiota reveals altered callosal myelination and white matter plasticity in a model of Huntington disease. Neurobiol Dis. 2019;127:65–75.

    Article  CAS  PubMed  Google Scholar 

  285. Kong G, Cao KL, Judd LM, Li S, Renoir T, Hannan AJ. Microbiome profiling reveals gut dysbiosis in a transgenic mouse model of Huntington’s disease. Neurobiol Dis. 2020;135:104268.

    Article  CAS  PubMed  Google Scholar 

  286. Alonso R, Pisa D, Carrasco L. Brain microbiota in Huntington’s disease patients. Front Microbiol. 2019;10:2622.

    Article  PubMed  PubMed Central  Google Scholar 

  287. Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M, Ince PG, Lin C, Miller RG, Mitsumoto H, Nicholson G, Ravits J, Shaw PJ, Swash M, Talbot K, Traynor BJ, Van den Berg LH, Veldink JH, Vucic S, Kiernan MC. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 2013;12:310–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Wu S, Yi J, Zhang YG, Zhou J, Sun J. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol Rep. 2015;3:e12356.

    Article  PubMed  PubMed Central  Google Scholar 

  289. Zhang YG, Wu S, Yi J, Xia Y, Jin D, Zhou J, Sun J. Target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis. Clin Ther. 2017;39:322–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Blacher E, Bashiardes S, Shapiro H, Rothschild D, Mor U, Dori-Bachash M, Kleimeyer C, Moresi C, Harnik Y, Zur M, Zabari M, Brik RB, Kviatcovsky D, Zmora N, Cohen Y, Bar N, Levi I, Amar N, Mehlman T, Brandis A, Biton I, Kuperman Y, Tsoory M, Alfahel L, Harmelin A, Schwartz M, Israelson A, Arike L, Johansson MEV, Hansson GC, Gotkine M, Segal E, Elinav E. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature. 2019;572:474–80.

    Article  CAS  PubMed  Google Scholar 

  291. Fang X. Potential role of gut microbiota and tissue barriers in Parkinson’s disease and amyotrophic lateral sclerosis. Int J Neurosci. 2016;126:771–6.

    Article  CAS  PubMed  Google Scholar 

  292. Zhai CD, Zheng JJ, An BC, Huang HF, Tan ZC. Intestinal microbiota composition in patients with amyotrophic lateral sclerosis: establishment of bacterial and archaeal communities analyses. Chin Med J. 2019;132:1815–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Brenner D, Hiergeist A, Adis C, Mayer B, Gessner A, Ludolph AC, Weishaupt JH. The fecal microbiome of ALS patients. Neurobiol Aging. 2018;61:132–7.

    Article  PubMed  Google Scholar 

  294. Bastiaanssen TFS, Cussotto S, Claesson MJ, Clarke G, Dinan TG, Cryan JF. Gutted! Unraveling the role of the microbiome in major depressive disorder. Harv Rev Psychiatry. 2020;28:26–39.

    Article  PubMed  PubMed Central  Google Scholar 

  295. Huang Y, Shi X, Li Z, Shen Y, Shi X, Wang L, Li G, Yuan Y, Wang J, Zhang Y, Zhao L, Zhang M, Kang Y, Liang Y. Possible association of Firmicutes in the gut microbiota of patients with major depressive disorder. Neuropsychiatr Dis Treat. 2018;14:3329–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Milaneschi Y, Kappelmann N, Ye Z, Lamers F, Moser S, Jones PB, Burgess S, Penninx B, Khandaker GM. Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts. Mol Psychiatry. 2021;26(12):7393–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Naseribafrouei A, Hestad K, Avershina E, Sekelja M, Linlokken A, Wilson R, Rudi K. Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil. 2014;26:1155–62.

    Article  CAS  PubMed  Google Scholar 

  298. Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, Zeng L, Chen J, Fan S, Du X, Zhang X, Yang D, Yang Y, Meng H, Li W, Melgiri ND, Licinio J, Wei H, Xie P. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21:786–96.

    Article  CAS  PubMed  Google Scholar 

  299. Valles-Colomer M, Falony G, Darzi Y, Tigchelaar EF, Wang J, Tito RY, Schiweck C, Kurilshikov A, Joossens M, Wijmenga C, Claes S, Van Oudenhove L, Zhernakova A, Vieira-Silva S, Raes J. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019;4:623–32.

    Article  CAS  PubMed  Google Scholar 

  300. Bosch JA, Nieuwdorp M, Zwinderman AH, Deschasaux M, Radjabzadeh D, Kraaij R, Davids M, de Rooij SR, Lok A. The gut microbiota and depressive symptoms across ethnic groups. Nat Commun. 2022;13:7129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Radjabzadeh D, Bosch JA, Uitterlinden AG, Zwinderman AH, Ikram MA, Van Meurs JBJ, Luik AI, Nieuwdorp M, Lok A, Van Duijn CM, Kraaij R, Amin N. Gut microbiome-wide association study of depressive symptoms. Nat Commun. 2022;13:7128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Long-Smith C, O’Riordan KJ, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota-gut-brain axis: new therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2020;60:477–502.

    Article  CAS  PubMed  Google Scholar 

  303. Sarkar A, Lehto SM, Harty S, Dinan TG, Cryan JF, Burnet PWJ. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci. 2016;39:763–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, Jafari P, Akbari H, Taghizadeh M, Memarzadeh MR, Asemi Z, Esmaillzadeh A. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial. Nutrition. 2016;32:315–20.

    Article  CAS  PubMed  Google Scholar 

  305. Slykerman RF, Hood F, Wickens K, Thompson JMD, Barthow C, Murphy R, Kang J, Rowden J, Stone P, Crane J, Stanley T, Abels P, Purdie G, Maude R, Mitchell EA, Probiotic in Pregnancy Study Group. Effect of Lactobacillus rhamnosus HN001 in pregnancy on postpartum symptoms of depression and anxiety: a randomised double-blind placebo-controlled trial. EBioMedicine. 2017;24:159–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Kazemi A, Soltani S, Ghorabi S, Keshtkar A, Daneshzad E, Nasri F, Mazloomi SM. Effect of probiotic and synbiotic supplementation on inflammatory markers in health and disease status: a systematic review and meta-analysis of clinical trials. Clin Nutr. 2020;39:789–819.

    Article  CAS  PubMed  Google Scholar 

  307. Foster JA, Mcvey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12.

    Article  CAS  PubMed  Google Scholar 

  308. Malan-Muller S, Valles-Colomer M, Raes J, Lowry CA, Seedat S, Hemmings SMJ. The gut microbiome and mental health: implications for anxiety- and trauma-related disorders. OMICS. 2018;22:90–107.

    Article  CAS  PubMed  Google Scholar 

  309. Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108:3047–52.

    Article  PubMed  Google Scholar 

  310. Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011;23:255–64.e119.

    Article  CAS  PubMed  Google Scholar 

  311. Crumeyrolle-Arias M, Jaglin M, Bruneau A, Vancassel S, Cardona A, Dauge V, Naudon L, Rabot S. Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology. 2014;42:207–17.

    Article  CAS  PubMed  Google Scholar 

  312. Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141:599–609, 609 e1–3.

    Article  CAS  PubMed  Google Scholar 

  313. McGuinness AJ, Davis JA, Dawson SL, Loughman A, Collier F, O’Hely M, Simpson CA, Green J, Marx W, Hair C, Guest G, Mohebbi M, Berk M, Stupart D, Watters D, Jacka FN. A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia. Mol Psychiatry. 2022;27:1920–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Madan A, Thompson D, Fowler JC, Ajami NJ, Salas R, Frueh BC, Bradshaw MR, Weinstein BL, Oldham JM, Petrosino JF. The gut microbiota is associated with psychiatric symptom severity and treatment outcome among individuals with serious mental illness. J Affect Disord. 2020;264:98–106.

    Article  CAS  PubMed  Google Scholar 

  315. Collins S, Hoare E, Allender S, Olive L, Leech RM, Winpenny EM, Jacka F, Lotfalian M. A longitudinal study of lifestyle behaviours in emerging adulthood and risk for symptoms of depression, anxiety, and stress. J Affect Disord. 2023;327:244–53.

    Article  PubMed  Google Scholar 

  316. Colica C, Avolio E, Bollero P, Costa de Miranda R, Ferraro S, Sinibaldi Salimei P, De Lorenzo A, Di Renzo L. Evidences of a new psychobiotic formulation on body composition and anxiety. Mediators Inflamm. 2017;2017:5650627.

    Article  PubMed  PubMed Central  Google Scholar 

  317. Messaoudi M, Violle N, Bisson JF, Desor D, Javelot H, Rougeot C. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011;2:256–61.

    Article  PubMed  Google Scholar 

  318. Rao AV, Bested AC, Beaulne TM, Katzman MA, Iorio C, Berardi JM, Logan AC. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009;1:6.

    Article  PubMed  PubMed Central  Google Scholar 

  319. Chong HX, Yusoff NAA, Hor YY, Lew LC, Jaafar MH, Choi SB, Yusoff MSB, Wahid N, Abdullah M, Zakaria N, Ong KL, Park YH, Liong MT. Lactobacillus plantarum DR7 alleviates stress and anxiety in adults: a randomised, double-blind, placebo-controlled study. Benefic Microbes. 2019;10:355–73.

    Article  CAS  Google Scholar 

  320. Cussotto S, Sandhu KV, Dinan TG, Cryan JF. The neuroendocrinology of the microbiota-gut-brain axis: a behavioural perspective. Front Neuroendocrinol. 2018;51:80–101.

    Article  CAS  PubMed  Google Scholar 

  321. Maier L, Pruteanu M, Kuhan M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  322. Castro-Nallar E, Bendall ML, Perez-Losada M, Sabuncyan S, Severance EG, Dickerson FB, Schroeder JR, Yolken RH, Crandall KA. Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls. PeerJ. 2015;3:e1140.

    Article  PubMed  PubMed Central  Google Scholar 

  323. Zheng P, Zeng B, Liu M, Chen J, Pan J, Han Y, Liu Y, Cheng K, Zhou C, Wang H, Zhou X, Gui S, Perry SW, Wong ML, Licinio J, Wei H, Xie P. The gut microbiome from patients with schizophrenia modulates the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv. 2019;5:eaau8317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  324. Zhu F, Ju Y, Wang W, Wang Q, Guo R, Ma Q, Sun Q, Fan Y, Xie Y, Yang Z, Jie Z, Zhao B, Xiao L, Yang L, Zhang T, Feng J, Guo L, He X, Chen Y, Chen C, Gao C, Xu X, Yang H, Wang J, Dang Y, Madsen L, Brix S, Kristiansen K, Jia H, Ma X. Metagenome-wide association of gut microbiome features for schizophrenia. Nat Commun. 2020;11:1612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  325. Olde Loohuis LM, Mangul S, Ori APS, Jospin G, Koslicki D, Yang HT, Wu T, Boks MP, Lomen-Hoerth C, Wiedau-Pazos M, Cantor RM, de Vos WM, Kahn RS, Eskin E, Ophoff RA. Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia. Transl Psychiatry. 2018;8:96.

    Article  PubMed  PubMed Central  Google Scholar 

  326. Schwarz E, Maukonen J, Hyytiainen T, Kieseppa T, Oresic M, Sabunciyan S, Mantere O, Saarela M, Yolken R, Suvisaari J. Analysis of microbiota in first episode psychosis identifies preliminary associations with symptom severity and treatment response. Schizophr Res. 2018;192:398–403.

    Article  PubMed  Google Scholar 

  327. Nguyen TT, Kosciolek T, Maldonado Y, Daly RE, Martin AS, McDonald D, Knight R, Jeste DV. Differences in gut microbiome composition between persons with chronic schizophrenia and healthy comparison subjects. Schizophr Res. 2019;204:23–9.

    Article  PubMed  Google Scholar 

  328. Dickerson FB, Stallings C, Origoni A, Katsafanas E, Savage CL, Schweinfurth LA, Goga J, Khushalani S, Yolken RH. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;16:PCC.13m01579.

    PubMed  PubMed Central  Google Scholar 

  329. Severance EG, Gressitt KL, Stallings CR, Katsafanas E, Schweinfurth LA, Savage CLG, Adamos MB, Sweeney KM, Origoni AE, Khushalani S, Dickerson FB, Yolken RH. Probiotic normalization of Candida albicans in schizophrenia: a randomized, placebo-controlled, longitudinal pilot study. Brain Behav Immun. 2017;62:41–5.

    Article  PubMed  Google Scholar 

  330. Ghaderi A, Banafshe HR, Mirhosseini N, Moradi M, Karimi MA, Mehrzad F, Bahmani F, Asemi Z. Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients. BMC Psychiatry. 2019;19:77.

    Article  PubMed  PubMed Central  Google Scholar 

  331. Okubo R, Koga M, Katsumata N, Odamaki T, Matsuyama S, Oka M, Narita H, Hashimoto N, Kusumi I, Xiao J, Matsuoka YJ. Effect of bifidobacterium breve A-1 on anxiety and depressive symptoms in schizophrenia: a proof-of-concept study. J Affect Disord. 2019;245:377–85.

    Article  PubMed  Google Scholar 

  332. Enck P, Aziz Q, Barbara G, Farmer AD, Fukudo S, Mayer EA, Niesler B, Quigley EM, Rajilic-Stojanovic M, Schemann M, Schwille-Kiuntke J, Simren M, Zipfel S, Spiller RC. Irritable bowel syndrome. Nat Rev Dis Primers. 2016;2:16014.

    Article  PubMed  PubMed Central  Google Scholar 

  333. Rodino-Janeiro BK, Vicario M, Alonso-Cotoner C, Pascua-Garcia R, Santos J. A review of microbiota and irritable bowel syndrome: future in therapies. Adv Ther. 2018;35:289–310.

    Article  PubMed  PubMed Central  Google Scholar 

  334. Chong PP, Chin VK, Looi CY, Wong WF, Madhavan P, Yong VC. The microbiome and irritable bowel syndrome—a review on the pathophysiology, current research and future therapy. Front Microbiol. 2019;10:1136.

    Article  PubMed  PubMed Central  Google Scholar 

  335. Quigley EM. Bugs on the brain; brain in the gut—seeking explanations for common gastrointestinal symptoms. Ir J Med Sci. 2013;182:1–6.

    Article  CAS  PubMed  Google Scholar 

  336. El-Salhy M, Valeur J, Hausken T, Gunnar Hatlebakk J. Changes in fecal short-chain fatty acids following fecal microbiota transplantation in patients with irritable bowel syndrome. Neurogastroenterol Motil. 2021;33:e13983.

    Article  CAS  PubMed  Google Scholar 

  337. Rajilic-Stojanovic M, Jonkers DM, Salonen A, Hanevik K, Raes J, Jalanka J, de Vos WM, Manichanh C, Golic N, Enck P, Philippou E, Iraqi FA, Clarke G, Spiller RC, Penders J. Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am J Gastroenterol. 2015;110:278–87.

    Article  PubMed  PubMed Central  Google Scholar 

  338. Durban A, Abellan JJ, Jimenez-Hernandez N, Artacho A, Garrigues V, Ortiz V, Ponce J, Latorre A, Moya A. Instability of the faecal microbiota in diarrhoea-predominant irritable bowel syndrome. FEMS Microbiol Ecol. 2013;86:581–9.

    Article  CAS  PubMed  Google Scholar 

  339. Jeffery IB, O’Toole PW, Ohman L, Claesson MJ, Deane J, Quigley EM, Simren M. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut. 2012;61:997–1006.

    Article  PubMed  Google Scholar 

  340. Matto J, Maunuksela L, Kajander K, Palva A, Korpela R, Kassinen A, Saarela M. Composition and temporal stability of gastrointestinal microbiota in irritable bowel syndrome—a longitudinal study in IBS and control subjects. FEMS Immunol Med Microbiol. 2005;43:213–22.

    Article  PubMed  Google Scholar 

  341. Jalanka-Tuovinen J, Salojarvi J, Salonen A, Immonen O, Garsed K, Kelly FM, Zaitoun A, Palva A, Spiller RC, De Vos WM. Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut. 2014;63:1737–45.

    Article  PubMed  Google Scholar 

  342. Kerckhoffs AP, Samsom M, van der Rest ME, de Vogel J, Knol J, Ben-Amor K, Akkermans LM. Lower Bifidobacteria counts in both duodenal mucosa-associated and fecal microbiota in irritable bowel syndrome patients. World J Gastroenterol. 2009;15:2887–92.

    Article  PubMed  PubMed Central  Google Scholar 

  343. Ravichandar JD, Rutherford E, Chow C-ET, Han A, Yamamoto ML, Narayan N, Kaplan GG, Beck PL, Claesson MJ, Dabbagh K, Iwai S, Desantis TZ. Strain level and comprehensive microbiome analysis in inflammatory bowel disease via multi-technology meta-analysis identifies key bacterial influencers of disease. Front Microbiol. 2022;13:961020.

    Article  PubMed  PubMed Central  Google Scholar 

  344. Mawe GM, Coates MD, Moses PL. Review article: intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1067–76.

    Article  CAS  PubMed  Google Scholar 

  345. Camilleri M. Serotonin in the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes. 2009;16:53–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  346. Clarke G, Fitzgerald P, Cryan JF, Cassidy EM, Quigley EM, Dinan TG. Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort. BMC Gastroenterol. 2009;9:6.

    Article  PubMed  PubMed Central  Google Scholar 

  347. Clarke G, McKernan DP, Gaszner G, Quigley EM, Cryan JF, Dinan TG. A distinct profile of tryptophan metabolism along the kynurenine pathway downstream of toll-like receptor activation in irritable bowel syndrome. Front Pharmacol. 2012;3:90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  348. Fitzgerald P, Cassidy Eugene M, Clarke G, Scully P, Barry S, Quigley Eamonn MM, Shanahan F, Cryan J, Dinan Timothy G. Tryptophan catabolism in females with irritable bowel syndrome: relationship to interferon-gamma, severity of symptoms and psychiatric co-morbidity. Neurogastroenterol Motil. 2008;20:1291–7.

    Article  CAS  PubMed  Google Scholar 

  349. Jeffery IB, Das A, O’Herlihy E, Coughlan S, Cisek K, Moore M, Bradley F, Carty T, Pradhan M, Dwibedi C, Shanahan F, O’Toole PW. Differences in fecal microbiomes and metabolomes of people with vs without irritable bowel syndrome and bile acid malabsorption. Gastroenterology. 2020;158:1016–28.e8.

    Article  CAS  PubMed  Google Scholar 

  350. Kennedy PJ, Clarke G, Quigley EM, Groeger JA, Dinan TG, Cryan JF. Gut memories: towards a cognitive neurobiology of irritable bowel syndrome. Neurosci Biobehav Rev. 2012;36:310–40.

    Article  PubMed  Google Scholar 

  351. Kennedy PJ, Cryan JF, Quigley EM, Dinan TG, Clarke G. A sustained hypothalamic-pituitary-adrenal axis response to acute psychosocial stress in irritable bowel syndrome. Psychol Med. 2014;44:3123–34.

    Article  CAS  PubMed  Google Scholar 

  352. Clarke G, Cryan JF, Dinan TG, Quigley EM. Review article: probiotics for the treatment of irritable bowel syndrome—focus on lactic acid bacteria. Aliment Pharmacol Ther. 2012;35:403–13.

    Article  CAS  PubMed  Google Scholar 

  353. Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018;48:1044–60.

    Article  PubMed  Google Scholar 

  354. Diop L, Guillou S, Durand H. Probiotic food supplement reduces stress-induced gastrointestinal symptoms in volunteers: a double-blind, placebo-controlled, randomized trial. Nutr Res. 2008;28:1–5.

    Article  CAS  PubMed  Google Scholar 

  355. Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, Traynor J, Gregory C, De Palma G, Pigrau M, Ford AC, Macri J, Berger B, Bergonzelli G, Surette MG, Collins SM, Moayyedi P, Bercik P. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology. 2017;153:448–59.e8.

    Article  PubMed  Google Scholar 

  356. Ticinesi A, Milani C, Lauretani F, Nouvenne A, Mancabelli L, Lugli GA, Turroni F, Duranti S, Mangifesta M, Viappiani A, Ferrario C, Magagio M, Ventura M, Meschi T. Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. Sci Rep. 2017;7:11102.

    Article  PubMed  PubMed Central  Google Scholar 

  357. Dinan TG, Cryan JF. Gut-brain axis in 2016: brain-gut-microbiota axis—mood, metabolism and behaviour. Nat Rev Gastroenterol Hepatol. 2017;14:69–70.

    Article  CAS  PubMed  Google Scholar 

  358. Halkjaer SI, Christensen AH, Lo BZS, Browne PD, Gunther S, Hansen LH, Petersen AM. Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. Gut. 2018;67:2107–15.

    Article  CAS  PubMed  Google Scholar 

  359. Mizuno S, Masaoka T, Naganuma M, Kishimoto T, Kitazawa M, Kurokawa S, Nakashima M, Takeshita K, Suda W, Mimura M, Hattori M, Kanai T. Bifidobacterium-rich fecal donor may be a positive predictor for successful fecal microbiota transplantation in patients with irritable bowel syndrome. Digestion. 2017;96:29–38.

    Article  PubMed  Google Scholar 

  360. Pimentel M, Morales W, Chua K, Barlow G, Weitsman S, Kim G, Amichai MM, Pokkunuri V, Rook E, Mathur R, Marsh Z. Effects of rifaximin treatment and retreatment in nonconstipated IBS subjects. Dig Dis Sci. 2011;56:2067–72.

    Article  CAS  PubMed  Google Scholar 

  361. Rea K, O’Mahony S, Dinan TG, Cryan JF. Pain bugs: gut microbiota and pain disorders. Curr Opin Physiol. 2019;11:97–102.

    Article  Google Scholar 

  362. Pusceddu MM, Gareau MG. Visceral pain: gut microbiota, a new hope? J Biomed Sci. 2018;25:73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  363. Holzer P, Farzi A, Hassan AM, Zenz G, Jacan A, Reichmann F. Visceral inflammation and immune activation stress the brain. Front Immunol. 2017;8:1613.

    Article  PubMed  PubMed Central  Google Scholar 

  364. Conte MP, Schippa S, Zamboni I, Penta M, Chiarini F, Seganti L, Osborn J, Falconieri P, Borrelli O, Cucchiara S. Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease. Gut. 2006;55:1760–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  365. Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, Nalin R, Jarrin C, Chardon P, Marteau P, Roca J, Dore J. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut. 2006;55:205–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  366. Noor SO, Ridgway K, Scovell L, Kemsley EK, Lund EK, Jamieson C, Johnson IT, Narbad A. Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of the gut microbiota. BMC Gastroenterol. 2010;10:134.

    Article  PubMed  PubMed Central  Google Scholar 

  367. Shankar V, Homer D, Rigsbee L, Khamis HJ, Michail S, Raymer M, Reo NV, Paliy O. The networks of human gut microbe-metabolite associations are different between health and irritable bowel syndrome. ISME J. 2015;9:1899–903.

    Article  PubMed  PubMed Central  Google Scholar 

  368. Crouzet L, Gaultier E, Del’Homme C, Cartier C, Delmas E, Dapoigny M, Fioramonti J, Bernalier-Donadille A. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogastroenterol Motil. 2013;25:e272–82.

    Article  CAS  PubMed  Google Scholar 

  369. Bennet JD, Brinkman M. Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet. 1989;1:164.

    Article  CAS  PubMed  Google Scholar 

  370. Ding C, Fan W, Gu L, Tian H, Ge X, Gong J, Nie Y, Li N. Outcomes and prognostic factors of fecal microbiota transplantation in patients with slow transit constipation: results from a prospective study with long-term follow-up. Gastroenterol Rep (Oxf). 2018;6:101–7.

    Article  PubMed  Google Scholar 

  371. Holvoet T, Joossens M, Wang J, Boelens J, Verhasselt B, Laukens D, van Vlierberghe H, Hindryckx P, De Vos M, De Looze D, Raes J. Assessment of faecal microbial transfer in irritable bowel syndrome with severe bloating. Gut. 2017;66:980–2.

    Article  PubMed  Google Scholar 

  372. Kellermayer R, Nagy-Szakal D, Harris RA, Luna RA, Pitashny M, Schady D, Mir SA, Lopez ME, Gilger MA, Belmont J, Hollister EB, Versalovic J. Serial fecal microbiota transplantation alters mucosal gene expression in pediatric ulcerative colitis. Am J Gastroenterol. 2015;110:604–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  373. Knox NC, Forbes JD, Van Domselaar G, Bernstein CN. The gut microbiome as a target for IBD treatment: are we there yet? Curr Treat Options Gastroenterol. 2019;17:115–26.

    Article  PubMed  Google Scholar 

  374. Naseer M, Poola S, Ali S, Samiullah S, Tahan V. Prebiotics and probiotics in inflammatory bowel disease (IBD): where are we now and where are we going? Curr Clin Pharmacol. 2020;15(3):216–33.

    CAS  PubMed  Google Scholar 

  375. Amaral FA, Sachs D, Costa VV, Fagundes CT, Cisalpino D, Cunha TM, Ferreira SH, Cunha FQ, Silva TA, Nicoli JR, Vieira LQ, Souza DG, Teixeira MM. Commensal microbiota is fundamental for the development of inflammatory pain. Proc Natl Acad Sci U S A. 2008;105:2193–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  376. Dinic M, Pecikoza U, Djokic J, Stepanovic-Petrovic R, Milenkovic M, Stevanovic M, Filipovic N, Begovic J, Golic N, Lukic J. Exopolysaccharide produced by probiotic strain Lactobacillus paraplantarum BGCG11 reduces inflammatory hyperalgesia in rats. Front Pharmacol. 2018;9:1.

    Article  PubMed  PubMed Central  Google Scholar 

  377. Culligan EP, Sleator RD. Advances in the microbiome: applications to Clostridium difficile infection. J Clin Med. 2016;5:83.

    Article  PubMed  PubMed Central  Google Scholar 

  378. Levy AN, Allegretti JR. Insights into the role of fecal microbiota transplantation for the treatment of inflammatory bowel disease. Ther Adv Gastroenterol. 2019;12:1756284819836893.

    Article  Google Scholar 

  379. Derwa Y, Gracie DJ, Hamlin PJ, Ford AC. Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;46:389–400.

    Article  CAS  PubMed  Google Scholar 

  380. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. elife. 2013;2:e01202.

    Article  PubMed  PubMed Central  Google Scholar 

  381. Lowe J, Briggs A, Whittle S, Hoon E, Stephenson M. Effectiveness of probiotics in the management of inflammatory arthritis: a systematic review protocol. JBI Database System Rev Implement Rep. 2018;16:2295–303.

    Article  PubMed  Google Scholar 

  382. Shen X, Yang H, Wu Y, Zhang D, Jiang H. Meta-analysis: association of Helicobacter pylori infection with Parkinson’s diseases. Helicobacter. 2017;22.

    Google Scholar 

  383. Osterlund P, Ruotsalainen T, Korpela R, Saxelin M, Ollus A, Valta P, Kouri M, Elomaa I, Joensuu H. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer. 2007;97:1028–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  384. Cai TT, Ye XL, Yong HJ, Song B, Zheng XL, Cui BT, Zhang FM, Lu YB, Miao H, Ding DF. Fecal microbiota transplantation relieve painful diabetic neuropathy: a case report. Medicine (Baltimore). 2018;97:e13543.

    Article  PubMed  PubMed Central  Google Scholar 

  385. De Roos NM, Van Hemert S, Rovers JMP, Smits MG, Witteman BJM. The effects of a multispecies probiotic on migraine and markers of intestinal permeability-results of a randomized placebo-controlled study. Eur J Clin Nutr. 2017;71:1455–62.

    Article  PubMed  Google Scholar 

  386. Meckel KR, Kiraly DD. A potential role for the gut microbiome in substance use disorders. Psychopharmacology. 2019;236:1513–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  387. Garcia-Cabrerizo R, Carbia C, Riordan KJO, Schellekens H, Cryan JF. Microbiota-gut-brain axis as a regulator of reward processes. J Neurochem. 2021;157:1495–524.

    Article  CAS  PubMed  Google Scholar 

  388. Peterson VL, Jury NJ, Cabrera-Rubio R, Draper LA, Crispie F, Cotter PD, Dinan TG, Holmes A, Cryan JF. Drunk bugs: chronic vapour alcohol exposure induces marked changes in the gut microbiome in mice. Behav Brain Res. 2017;323:172–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  389. Bajaj JS. Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16:235–46.

    Article  PubMed  Google Scholar 

  390. Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Starkel P, Windey K, Tremaroli V, Backhed F, Verbeke K, de Timary P, Delzenne NM. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A. 2014;111:E4485–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  391. Carbia C, Bastiaanssen TFS, Iannone LF, García-Cabrerizo R, Boscaini S, Berding K, Strain CR, Clarke G, Stanton C, Dinan TG, Cryan JF. The Microbiome-Gut-Brain axis regulates social cognition & craving in young binge drinkers. EBioMedicine. 2023;89:104442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  392. Lowe PP, Gyongyosi B, Satishchandran A, Iracheta-Vellve A, Cho Y, Ambade A, Szabo G. Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression. J Neuroinflammation. 2018;15:298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  393. Bull-Otterson L, Feng W, Kirpich I, Wang Y, Qin X, Liu Y, Gobejishvili L, Joshi-Barve S, Ayvaz T, Petrosino J, Kong M, Barker D, McClain C, Barve S. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS One. 2013;8:e53028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  394. Allais L, Kerckhof FM, Verschuere S, Bracke KR, De Smet R, Laukens D, Van den Abbeele P, De Vos M, Boon N, Brusselle GG, Cuvelier CA, Van de Wiele T. Chronic cigarette smoke exposure induces microbial and inflammatory shifts and mucin changes in the murine gut. Environ Microbiol. 2016;18:1352–63.

    Article  CAS  PubMed  Google Scholar 

  395. Biedermann L, Brulisauer K, Zeitz J, Frei P, Scharl M, Vavricka SR, Fried M, Loessner MJ, Rogler G, Schuppler M. Smoking cessation alters intestinal microbiota: insights from quantitative investigations on human fecal samples using FISH. Inflamm Bowel Dis. 2014;20:1496–501.

    Article  PubMed  Google Scholar 

  396. Lee K, Vuong HE, Nusbaum DJ, Hsiao EY, Evans CJ, Taylor AMW. The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence. Neuropsychopharmacology. 2018;43:2606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  397. Lowe PP, Gyongyosi B, Satishchandran A, Iracheta-Vellve A, Ambade A, Kodys K, Catalano D, Ward DV, Szabo G. Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. PLoS One. 2017;12:e0174544.

    Article  PubMed  PubMed Central  Google Scholar 

  398. Plein LM, Rittner HL. Opioids and the immune system—friend or foe. Br J Pharmacol. 2018;175:2717–25.

    Article  CAS  PubMed  Google Scholar 

  399. Wang F, Meng J, Zhang L, Johnson T, Chen C, Roy S. Morphine induces changes in the gut microbiome and metabolome in a morphine dependence model. Sci Rep. 2018;8:3596.

    Article  PubMed  PubMed Central  Google Scholar 

  400. Cluny NL, Keenan CM, Reimer RA, Le Foll B, Sharkey KA. Prevention of diet-induced obesity effects on body weight and gut microbiota in mice treated chronically with delta9-tetrahydrocannabinol. PLoS One. 2015;10:e0144270.

    Article  PubMed  PubMed Central  Google Scholar 

  401. Fields CT, Sampson TR, Bruce-Keller AJ, Kiraly DD, Hsiao EY, de Vries GJ. Defining dysbiosis in disorders of movement and motivation. J Neurosci. 2018;38:9414–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  402. Kiraly DD, Walker DM, Calipari ES, Labonte B, Issler O, Pena CJ, Ribeiro EA, Russo SJ, Nestler EJ. Alterations of the host microbiome affect behavioral responses to cocaine. Sci Rep. 2016;6:35455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  403. García-Cabrerizo R, Barros-Santos T, Campos D, Cryan JF. The gut microbiota alone and in combination with a social stimulus regulates cocaine reward in the mouse. Brain Behav Immun. 2023;107:286–91.

    Article  PubMed  Google Scholar 

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Lynch, C.M.K., O’Riordan, K.J., Clarke, G., Cryan, J.F. (2023). Gut Microbes: The Gut Brain Connection. In: Pimentel, M., Mathur, R., Barlow, G.M. (eds) Clinical Understanding of the Human Gut Microbiome. Springer, Cham. https://doi.org/10.1007/978-3-031-46712-7_4

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